Colonization of bacteria on the surfaces of medical devices and healthcare products, particularly in implanted devices, result in serious patient problems, including the need to remove and/or replace the implanted device and to vigorously treat secondary infection conditions. Considerable efforts, therefore, have been directed toward preventing such colonization by the use of antimicrobial agents, such as antibiotics, that are bound to the surface of the materials used in such medical devices. The focus of prior attempts has been to produce a sufficient bacteriostatic or bactericidal action to prevent microbial colonization on the device surface.
As a defense against antimicrobial agents that would affect their survival and proliferation, many surface adhered microorganisms form a defense layer comprising a muco-polysaccharide film called biofilm. Formation of biofilms on the surface of medical devices can be detrimental to the integrity of the medical device, present health risks, and prevent sufficient flow through the lumens of medical devices. Furthermore, biofilms formed on the device surface recruit non-adhered or “sessile” microorganisms from the device environment, such as urine or blood, and enable their propagation. Particulate biofilm matter that periodically detach from the surface of a medical device or healthcare product, for example, therefore provide, a continued source of pathologically infectious microorganisms that can contaminate the physiological environment in which the medical device or healthcare product is in contact with, that can result in serious secondary infections in patients.
Although coating or cleaning medical devices with antimicrobial agents, such as antibiotics or antiseptics, can be effective in killing or inhibiting growth of free-floating or “planktonic” organisms not adhered to the device surface, such antimicrobial agents are generally much less active against the microorganisms that are deeply embedded within the biofilm due to their inability to penetrate the biofilm. The failure of the antimicrobial agents to sufficiently remove the microorganisms is therefore largely due to the protective effect of the biofilm which prevents diffusion of antimicrobial deep into the biofilm layer to eliminate the microorganisms proliferating therein.
Biofilm associated problems experienced with implantable medical devices such as catheters, particularly catheters designed for urinary tract infections, pose a significant risk for catheterized patients of acquiring secondary infection such as nosocomial infection in a hospital environment. Such infections can result in prolonged hospital stay, administration of additional antibiotics, and increased cost of post-operative hospital care. In biofilm mediated urinary-tract infections, bacteria are believed to gain access to the catheterized bladder by migration from the collection bag, from the catheter by adhering to and proliferating on the material constituting the catheter material, or by ascending the periurethral space outside the catheter. Although, the use of antimicrobially coated catheters wherein antibiotic agents or antimicrobial compounds are dispersed within the coating have been reported to reduce the incidence of catheter associated bacteriuria, such coatings have proven to be largely ineffective in preventing bacterial adhesion and biofilm formation on the catheter surface for extended periods, and therefore do not sufficiently retard the onset of bacterial infection.
The use of silver compounds in antimicrobial coatings for medical devices is known in the art. The antiseptic activity of silver compounds is a well-known property that has been utilized for many years in topical formulations. Silver is known to possess antibacterial properties and is used topically either as a metal or as silver salts due to their ability to generate bactericidal amounts of silver ions (Ag+), in which in this bioactive species, is released to the contacting environment. The bactericidal and fungistatic effect of the silver ion have been extensively utilized clinically; for example, silver nitrate, which is readily soluble (highly ionizable) in water, at concentrations of 0.5-1% exhibits disinfectant properties and is used for preventing infections in burns or for prophylaxis of neonatal conjunctivitis. Silver nitrate however, can cause toxic side effects at these concentrations, and does cause discoloration of the skin (Argyria).
A specific advantage in using the silver ion as an antibacterial agent is the inability of bacteria to acquire tolerance to the silver ion, which is in contrast to many types of antibiotics. Unlike antibiotics, the potential for bacteria to become silver ion resistant is therefore quite low. However, it is also recognized that silver compounds capable of providing bactericidal levels of silver ion have reduced photostability, and tend to discolor in the presence of light and/or heat as a result of photoreduction of Ag+ ion to metallic silver. Furthermore, commonly used terminal sterilization processes such as gamma or e-beam radiation of coatings or formulations containing such silver compounds results in discoloration and loss of activity in such materials, whether it is in the form of a cream, gel or as a coating on a medical device. Silver compounds that have extremely low solubility in aqueous solutions such as silver iodide (Ksp˜10−18) and silver sulfide (Ksp˜10−52) on the other hand, are relatively more photostable but poorly ionized, and hence cannot provide bactericidal levels of silver ions into the contacting environment. They are, therefore, either weakly antibacterial (bacteriostatic), or inert.
Silver compounds with relatively low aqueous solubilities but sufficient ionization such as silver oxide (Ag2O) and silver chloride (AgCl) (Ksp 10−8 to 10−9) are weakly antibacterial and have been used in antimicrobial coatings. However, they are incorporated as micronized particles suspended within the coating which effectively reduces the effective concentration of Ag+ ions released from such coatings, resulting in shorter coating efficiency and greater tendency to fail in bacterially rich or growth promoting environments. Silver sulfadiazine (AgSD), a substantially water insoluble compound (Ksp˜10−9) has a combination of a weakly antibacterial sulfadiazine molecule that is complexed with silver. In contrast to silver nitrate, the solubility of the silver sulfadiazine complex is relatively low, and hence both silver ion and sulfadiazine are present only in low concentrations in aqueous solutions. The antibacterial effect of AgSD in topical formulations may, therefore, persist over a longer period of time before being washed out at topically treated wound sites. AgSD is, therefore, used in the treatment of wounds, particularly for burns, under the trademarks Silvadene® and Flamazine®. The substantially low water solubility of AgSD has however, limited its use in antimicrobial coatings, particularly in thin coatings for medical devices. Attempts to incorporate AgSD into antimicrobial coatings involve dispersion AgSD as micronized particles within relatively hydrophilic polymeric coating materials such as polyethyleneglycol (PEG) and polyvinylalcohol (PVA) which significantly limits the ability to obtain high AgSD concentrations in thin coatings, without compromising coating integrity and mechanical properties. European patent application EP 83305570 discloses a polyvinylpyrollidone hydrogel containing micronized AgSD and cross-linked by e-beam radiation used as an absorbent wound dressing. Such hydrogel absorbent materials are, however, not suitable for coating of medical devices in which high loading of particulate AgSD is not achievable. Furthermore, the antimicrobial efficacy of such coatings is relatively poor because of the relatively low concentrations of silver (Ag+) ions in the coating, and such coatings therefore require additional water-soluble antimicrobial compounds, such as chlorhexidine to provide bactericidal levels of antimicrobial agents in the contacting environment. Such increased elution of the non-silver agent, however, is likely to adversely affect the duration of coating efficacy, since the coating becomes depleted of the soluble agent in a relatively short period of time. Such antimicrobial coatings, therefore, are not optimal for medical devices that remain implanted in the patient for longer periods of time (several days to weeks).